Dietary fat, CCK and the cholinergic antiinflammatory pathway

Background

One of the most important antiinflammatory pathways is mediated by the vagus nerve. Vagal stimulation increases the release of acetylcholine, which then interacts with the alpha 7 subunit of the nicotinic receptor on macrophages, activating the Jak2-STAT3 signaling pathway (1). This interaction inhibits macrophage activation and thus reduces inflammation. This pathway is known as the cholinergic antiinflammatory pathway (CAP)*. Stimulation of CAP has been shown to reduce TNF-a, IL-1b, IL-6 and IL-18 levels during endotoxemia (2) and NF-kB activation (3). The autonomic nervous system controls inflammation by the adrenergic pro-inflammatory pathway and the CAP (4):

Nature Reviews Immunology 8, 776-787

Although there are different ways to stimulate the CAP, most research has been done either using electrical stimulation (or acetylcholine receptor agonists) or vagotomy in laboratory animals. As nutrition is a determinant factor contributing or reducing inflammation, it seems plausible to speculate about the role of different nutrients modulating the CAP.  

Luyer et al (5) tested the ability of dietary fat to modulate inflammation, by stimulating the release of cholecystokinin (CCK). They induced hemorragic shock in Sprague-Dawley rats, in order to increase proinflammatory cytokines such as IL-6 and TNF-a. They fed them either a low fat or high fat enteral nutrition, or fasting. Additionally, high-fat fed rats were vagotomized (VGX) or sham vagotomized (Sham). Nutritional composition of both diets was as follows, as percentage of total energy:

High fat: 6.9% protein, 40.9% carbohydrate, 52.2% fat.

Low fat: 6.9% protein, 75.4% carbohydrate, 16.7% fat.

Proteins were derived from lean milk and carbohydrates from a mixture of sucrose and corn starch. The lipid source was vegetable oil, cointaining 8.1% SFA, 58.9% MUFA (57.4% oleic acid), 28.2% PUFA (23% linoleic acid). The amount of n-3 and n-6 in the high fat nutrition was less than 5% of the total fat content. They found that:

- High-fat enteral nutrition reduced hemorragic shock-induced TNF-a and IL-6 in Sham rats, compared to low-fat and fasted controls. Vagotomy nearly abolished the fat-induced reduction in these proinflammatory cytokines (TNF-a: 205 +/-11 pg/ml [VGX] vs. 5 +/-1 pg/ml [Sham]; IL-6: 80 +/-5 pg/ml [VGX] vs. 19 +/-9 pg/ml [Sham]).

Intestinal barrier function was assessed by a. bacterial translocation to distant organs, b. leakage of horseradish peroxidase (HRP) in isolated ileum-segments and c. plasma endotoxin levels. Increased intestinal permeability and impairment of gut barrier function is observed after induction of hemorragic shock. According to the reduction in proinflammatory cytokines, the high-fat nutrition reduced endotoxemia, permeability of ileum segments for HRP and bacterial translocation to distant organs, compared to fasted and low-fat Sham rats. Vagotomy reversed the protection of the high-fat diet, elevating plasma endotoxin levels (from 12 +/- 2 pg/ml to 28 +/-1 pg/ml), increasing leakage of HRP (from 1.1 +/- 0.7ug/ml to 2.3 +/- 0.5ug/ml) and bacterial translocation (from 16 CFU/g tissue to 328 CFU/g). 

Using CCK-A and CCK-B receptor antagonists (or vehicle) in high-fat fed Sham rats, they showed that the protection from a high fat nutrition was mediated by CCK, as inhibition of CCK-A and CCK-B enhanced plasma TNF-a and IL-6 after hemorragic shock induction, as well as endotoxemia, HRP permeability and bacterial translocation to distant organs, compared to vehicle animals. Moreover, administration of chlorisondamine abrogated the inhibitory effects of a high-fat nutrition on the parameters previously evaluated, suggesting that inhibition of inflammation was mediated by stimulation of nicotinic receptors by way of efferent vagal fibers. The authors proposed the following model for explaining their observations:

The author's description is as follows:

"Ingestion of high amounts of fat induces release of cholecystokinin (CCK) that binds to CCK-A and CCK-B receptors (CCK-r) located centrally or on peripheral vagal afferents. Activation of CCK-receptors triggers vagal efferents leading to an increase of acetylcholine (Ach), the principal parasympathetic neurotransmitter. Release of inflammatory cytokines such as TNF-a and IL-6 after activation of Toll-like receptors by bacterial products is inhibited by way of binding of acetylcholine to a-7 nicotinic (a7-nAch) receptors."

The findings of this study are remarkable, but as far as I can see, there was not much practical application after it was published. It isnt surprising. The same authors have published studies showing that a high-fat enteral nutrition protects the liver from the remote effects of hemorragic shock (high-fat treated animals had minimal liver injury, no evidence of mtDNA damage and significantly lower expression of stress proteins) (6) and exposure to bacterial DNA (7), and have proposed the utilization of a high-fat enteral nutrition after sever trauma to attenuate the inflammatory response (8) and to treat inflammatory conditions (9).

Short after the publication of this paper, Tracey (10) expanded the findings of Luyer et al., proposing fat-induced activation of the CAP for the treatment of inflammatory diseases:

But controlled trials using this information is lacking. How can dietary fat, which is supposed to be inflammatory, can be anti-inflammatory? I guess that most nutrition researchers just ignore the awkward. Even recent papers dealing with the subject and the hypothesis of vagal nerve stimulation for treatment of inflammatory diseases do not mention anything about a high fat diet increasing the CAP. Moreover, you can find gems like this one, from a paper published in Medical Hypotheses recently by Undurti N. Das (11), called "Vagus nerve stimulation as a strategy to prevent and manage metabolic syndrome":

"It is proposed that consumption of energy dense food leads to acute raise in plasma glucose levels that triggers increased production of IL-6, TNF-a, and IL-18 by peripheral leukocytes, monocytes and macrophages [11]. Simultaneously, gut produces cholecystokinin that, in turn, enhances vagal tone and induces the release of acetylcholine [39]. Acetylcholine and the acute raise in plasma glucose levels trigger the release of insulin from pancreatic b cells that decrease plasma glucose levels and inhibit IL-6, TNF-a, and IL-18 secretion and thus, homeostasis is restored. However, this regulatory system quickly fades in the face of continued ingestion of a fat-rich and/or energy-dense diet. Thus, fat-rich (especially saturated fat rich) and energy-dense foods promote insulin resistance, obesity, type 2 diabetes mellitus and the metabolic syndrome, in part, by impairing nutrient-sensing systems that exist in the gut, liver and hypothalamus that are originally designed to limit food intake and enhance insulin sensitivity."

I find the statement "fat-rich (especially saturated fat rich) (...) foods promote..." misleading to say the least. In this regard, CCK could be a previously uncharacterized indirect antiinflammatory molecule. At the moment, this is highly speculative because the overall inflammation balance depends on several factors and not only stimulation of the CAP. 

* Or "inflammatory reflex".

Luyer MD, Greve JW, Hadfoune M, Jacobs JA, Dejong CH, & Buurman WA (2005). Nutritional stimulation of cholecystokinin receptors inhibits inflammation via the vagus nerve. The Journal of experimental medicine, 202 (8), 1023-9 PMID: 16216887